V007 1. NAME of the MEDICINAL PRODUCT Ezetimibe/ Simvastatin 10 Mg/10 Mg Tablets Ezetimibe/Simvastatin 10 Mg/20 Mg Tablets Ezeti
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1. NAME OF THE MEDICINAL PRODUCT Ezetimibe/ Simvastatin 10 mg/10 mg Tablets Ezetimibe/Simvastatin 10 mg/20 mg Tablets Ezetimibe/Simvastatin 10 mg/40 mg Tablets 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each tablet contains 10 mg ezetimibe and 10, 20 or 40 mg of simvastatin. Excipient(s) with known effect: Each 10 mg/10 mg tablet contains 57.225 mg of lactose monohydrate. Each 10 mg/20 mg tablet contains 124.450 mg of lactose monohydrate. Each 10 mg/40 mg tablet contains 258.900 mg of lactose monohydrate. For the full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM Tablet Ezetimibe/Simvastatin 10 mg /10 mg tablets are white to off white capsule-shaped uncoated tablets debossed with code “L” on one side and plain on the other side. The tablets have a length of about 8.50 mm and width of about 4.30 mm. Ezetimibe/Simvastatin 10 mg/20 mg tablets are white to off-white capsule-shaped uncoated tablets debossed with “I” on one side and plain on other side. The tablets have a length of about 10.70 mm and width of about 5.40 mm. Ezetimibe/Simvastatin 10 mg/40 mg tablets are white to off white capsule-shaped uncoated tablets debossed with code “F” on one side and plain on the other side. The tablets have a length of about 13.80 mm and width of about 6.00 mm. 4. CLINICAL PARTICULARS 4.1 Therapeutic indications Prevention of Cardiovascular Events Ezetimibe/Simvastatin is indicated to reduce the risk of cardiovascular events (see section 5.1) in patients with coronary heart disease (CHD) and a history of acute coronary syndrome (ACS), either previously treated with a statin or not. Hypercholesterolaemia Ezetimibe/Simvastatin tablets are indicated as adjunctive therapy to diet for use in patients with primary (heterozygous familial and non-familial) hypercholesterolaemia or mixed hyperlipidaemia where use of a combination product is appropriate: • patients not appropriately controlled with a statin alone • patients already treated with a statin and ezetimibe Homozygous Familial Hypercholesterolaemia (HoFH) Ezetimibe/Simvastatin tablets are indicated as adjunctive therapy to diet for use in patients with HoFH. Patients may also receive adjunctive treatments (e.g., low-density lipoprotein [LDL] apheresis). V007 4.2 Posology and method of administration Posology Hypercholesterolaemia The patient should be on an appropriate lipid-lowering diet and should continue on this diet during treatment with Ezetimibe/Simvastatin tablets. Route of administration is oral. The dosage range of Ezetimibe/Simvastatin tablets is 10/10 mg/day through 10/80 mg/day in the evening. All dosages may not be available in all member states. The typical dose is 10/20 mg/day or 10/40 mg/day given as a single dose in the evening. The 10/80 mg dose is only recommended in patients with severe hypercholesterolaemia and at high risk for cardiovascular complications who have not achieved their treatment goals on lower doses and when the benefits are expected to outweigh the potential risks (see section 4.4 and 5.1). The patient's low-density lipoprotein cholesterol (LDL-C) level, coronary heart disease risk status, and response to current cholesterol-lowering therapy should be considered when starting therapy or adjusting the dose. The dose of Ezetimibe/Simvastatin tablets should be individualised based on the known efficacy of the various dose strengths of Ezetimibe/Simvastatin tablets (see section 5.1, Table 1) and the response to the current cholesterol-lowering therapy. Adjustments of dosage, if required, should be made at intervals of not less than 4 weeks. Ezetimibe/Simvastatin tablets can be administered with or without food. The tablet should not be split. Patients with Coronary Heart Disease and ACS Event History In the cardiovascular events risk reduction study (IMPROVE-IT), the starting dose was 10/40 mg once a day in the evening. The 10/80-mg dose is only recommended when the benefits are expected to outweigh the potential risks. Homozygous Familial Hypercholesterolaemia The recommended starting dosage for patients with homozygous familial hypercholesterolaemia is Ezetimibe/Simvastatin tablets 10/40 mg/day in the evening. The 10/80-mg dose is only recommended when the benefits are expected to outweigh the potential risks (see above; section 4.3 and 4.4). Ezetimibe/Simvastatin tablets may be used as an adjunct to other lipid-lowering treatments (e.g., LDL apheresis) in these patients or if such treatments are unavailable. In patients taking lomitapide concomitantly with Ezetimibe/Simvastatin tablets, the dose of Ezetimibe/Simvastatin tablets must not exceed 10/40 mg/day (see sections 4.3, 4.4 and 4.5). Co-administration with other medicines Dosing of Ezetimibe/Simvastatin tablets should occur either ≥2 hours before or ≥4 hours after administration of a bile acid sequestrant. In patients taking amiodarone, amlodipine, verapamil, diltiazem, or products containing elbasvir or grazoprevir concomitantly with Ezetimibe/Simvastatin tablets, the dose of Ezetimibe/Simvastatin tablets should not exceed 10/20 mg/day (see sections 4.4 and 4.5). In patients taking lipid-lowering doses (≥ 1 g/day) of niacin concomitantly with Ezetimibe/Simvastatin tablets, the dose of Ezetimibe/Simvastatin tablets should not exceed 10/20 mg/day (see sections 4.4 and 4.5). V007 Elderly No dosage adjustment is required for elderly patients (see section 5.2). Paediatric population Initiation of treatment must be performed under review of a specialist. Adolescents ≥ 10 years (pubertal status: boys Tanner Stage II and above and girls who are at least one year post-menarche): The clinical experience in paediatric and adolescent patients (aged 10- 17 years old) is limited. The recommended usual starting dose is 10/10 mg once a day in the evening. The recommended dosing range is 10/10 to a maximum of 10/40 mg/day (see sections 4.4 and 5.2). Children < 10 years: Ezetimibe/Simvastatin tablets are not recommended for use in children below age 10 due to insufficient data on safety and efficacy (see section 5.2). The experience in pre-pubertal children is limited. Patients with Hepatic Impairment No dosage adjustment is required in patients with mild hepatic impairment (Child Pugh score 5 to 6). Treatment with Ezetimibe/Simvastatin tablets is not recommended in patients with moderate (Child Pugh score 7 to 9) or severe (Child Pugh score >9) liver dysfunction (see sections 4.4 and 5.2.). Patients with Renal Impairment No modification of dosage should be necessary in patients with mild renal impairment (estimated glomerular filtration rate ≥60 ml/min/1.73m²). In patients with chronic kidney disease and estimated glomerular filtration rate <60 ml/min/1.73m², the recommended dose of Ezetimibe/Simvastatin tablets is 10/20 mg once a day in the evening (see sections 4.4, 5.1 and 5.2). Higher doses should be implemented cautiously. Method of Administration Ezetimibe/Simvastatin tablets is for oral administration. Ezetimibe/Simvastatin can be administered as a single dose in the evening. 4.3 Contraindications Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1. Pregnancy and lactation (see section 4.6). Active liver disease or unexplained persistent elevations in serum transaminases. Concomitant administration of potent CYP3A4 inhibitors (agents that increase AUC approximately 5 fold or greater) (e.g.,itraconazole, ketoconazole, posaconazole, voriconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors (e.g. nelfinavir), boceprevir, telaprevir, nefazodone, and drugs containing cobicistat) (see sections 4.4 and 4.5). Concomitant administration of gemfibrozil, ciclosporin, or danazol (see section 4.4 and 4.5) In patients with HoFH, concomitant administration of lomitapide with doses > 10/40 mg Ezetimibe/Simvastatin tablets (see sections 4.2, 4.4 and 4.5). 4.4 Special warnings and precautions for use V007 Myopathy/Rhabdomyolysis In post-marketing experience with ezetimibe, cases of myopathy and rhabdomyolysis have been reported. Most patients who developed rhabdomyolysis were taking a statin concomitantly with ezetimibe. However, rhabdomyolysis has been reported very rarely with ezetimibe monotherapy and very rarely with the addition of ezetimibe to other agents known to be associated with increased risk of rhabdomyolysis. Ezetimibe/Simvastatin tablets contain simvastatin. Simvastatin, like other inhibitors of HMG- CoA reductase, occasionally causes myopathy manifested as muscle pain, tenderness or weakness with creatine kinase (CK) above 10X the upper limit of normal (ULN). Myopathy sometimes takes the form of rhabdomyolysis with or without acute renal failure secondary to myoglobinuria, and very rare fatalities have occurred. The risk of myopathy is increased by high levels of HMG- CoA reductase inhibitory activity in plasma (i.e., elevated simvastatin and simvastatin acid plasma levels), which may be due, in part, to interacting drugs that interfere with simvastatin metabolism and/or transporter pathways (see section 4.5). As with other HMG-CoA reductase inhibitors, the risk of myopathy/rhabdomyolysis is dose related for simvastatin. In a clinical trial database in which 41,413 patients were treated with simvastatin 24,747 (approximately 60 %) of whom were enrolled in studies with a median follow- up of at least 4 years, the incidence of myopathy was approximately 0.03%, 0.08% and 0.61% at 20, 40 and 80 mg/day, respectively. In these trials, patients were carefully monitored and some interacting medicinal products were excluded. In a clinical trial in which patients with a history of myocardial infarction were treated with simvastatin 80 mg/day (mean follow-up 6.7 years), the incidence of myopathy was approximately 1.0% compared with 0.02% for patients on 20 mg/day. Approximately half of these myopathy cases occurred during the first year of treatment. The incidence of myopathy during each subsequent year of treatment was approximately 0.1%.